Eculizumab and recurrent C3 glomerulonephritis

Background

Hyperactivity of the alternative complement pathway is the principle defect in C3 glomerulopathies (C3G). Eculizumab, a monoclonal antibody that binds C5 to prevent formation of the membrane attack complex, has been shown to be beneficial in some patients with this disease.

Methods

In this open-label, proof-of-concept efficacy-and-safety study, a patient with the initial diagnosis of dense deposit disease (DDD) and allograft recurrence of C3 glomerulonephritis (C3GN) was treated with eculizumab every other week for 1 year. The patient had pathological evidence of C3GN and proteinuria >1 g/day at enrollment. He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months.

Results

Although no mutations were identified in complement genes, functional studies were positive for C3 nephritic factors and elevated levels of soluble membrane attack complex (sMAC). On therapy, sMAC levels normalized and although proteinuria initially decreased, it increased reaching pre-treatment levels at 12 months. Although serum creatinine remained stable, repeat allograft biopsies showed progression of disease.

Conclusions

Clinical and histopathologic data suggest a partial response to eculizumab in this patient. While eculizumab blocked activation of the terminal complement cascade, persistent dysregulation of the alternative pathway remained, indicating eculizumab alone cannot control disease in this patient. Additional research is required to identify effective anticomplement therapy for this group of C3G patients.     

Left atrial abnormality by electrocardiogram predicts left ventricular hypertrophy by echocardiography in the presence of right bundle-branch block

Background: Left ventricular hypertrophy (LVH) on the electrocardiogram (ECG) may be masked in the presence of complete right bundle-branch block (RBBB). Left bundle-branch block on the ECG is associated with LVH at autopsy in 93% of hearts studied. However, RBBB does not predict LVH and the usual ECG criteria applied for LVH may not be reliable in the presence of RBBB. Hypothesis: The study was undertaken to evaluate left atrial (LA) abnormality as a criterion for the diagnosis of LVH in the presence of RBBB. Methods: Left atrial abnormality in the ECG was assessed by two independent observers as a criterion of LVH in the presence of RBBB in 100 patients, and data were compared with those of 50 patients without LA abnormality. Results: Left ventricular hypertrophy was confirmed by echocardiographic determination of left ventricular (LV) mass in both groups. Observers reliably differentiated between hy-pertrophied and normal-sized LV in the presence of RBBB by using LA abnormality as an ECG criterion when correlated with LV mass determined by echocardiography. Observer 1 correctly detected LVH in 88% and Observer 2 in 82% of patients. False positive diagnosis was made in 12 and 18% of patients by Observers 1 and 2, respectively. Observers' performance of recognition of LA abnormality in the present study was 94%. Results showed sensitivity of 76 and 70% and specificity of 84 and 92% for Observers 1 and 2, respectively. Left ventricular mass increased significantly and was diagnostic of LVH in 92% of patients with LA abnormality. Left ventricular mass was high in 84% of patients when corrected by body surface area. LVH in the presence of RBBB by the ECG was found in only seven patients (5%) when six commonly used conventional criteria of diagnosis of LVH by ECG were employed. Regression analysis found LA abnormality to be a strong independent predictor of increased LV mass. Multiple regression analysis revealed that age, body mass index, body surface area, and frontal axis are also significant predictors of LV mass. Conclusion: The results obtained by the correlation of LA abnormality by ECG and LVH by echocardiography conclude that LA abnormality by ECG was significantly diagnostic of LV hypertrophy in the presence of RBBB.     

Socioeconomic Position and Factors Associated With Use of a Nonsupine Infant Sleep Position: Findings From the Canadian Maternity Experiences Survey

Objectives. With a focus on socioeconomic position, we examined the association between maternal education and nonsupine infant sleep position, and examined patterns of effect modification with additional sociodemographic, maternal, infant, and health services predictors.Methods. Data were from the Maternity Experiences Survey, a national population-based sample of 76 178 new Canadian mothers (unweighted n = 6421) aged 15 years or older interviewed in 2006–2007. Using logistic regression, we developed multivariate models for 3 maternal education strata.Results. Level of maternal education was significantly and inversely related to nonsupine infant sleep position. Stratified analyses revealed different predictive factors for nonsupine infant sleep position across strata of maternal education. Postpartum home visits were not associated with use of this sleep position among new mothers with less than high school completion. Adequacy of postpartum information regarding sudden infant death syndrome was not associated with nonsupine infant sleep position in any of the educational strata.Conclusions. These findings suggest a need to revisit Back to Sleep health promotion strategies and to ensure that these interventions are tailored to match the information needs of all families, including mothers with lower levels of formal education.Optimizing infant sleep position in an effort to reduce the incidence of sudden infant death syndrome (SIDS) has been an important maternal child health promotion strategy since nonsupine sleep position was identified as an important modifiable risk factor for SIDS in the early 1990s.1 Dramatic decreases in SIDS rates in many countries over the subsequent decade2–5 were largely credited to the success of public health campaigns that initially advised that infants be placed in nonprone positions for sleep and later restricted the recommendation to the supine sleep position only.5–10 In Canada and the United States, SIDS rates dropped by 70% and 60%, respectively, between 1985 and 2004.2,5,6,11 These reductions in SIDS rates were accompanied by reductions in postneonatal mortality rates, suggesting that they were real reductions rather than artifacts of changes in diagnostic criteria or coding practices.5More recently, SIDS rates have stabilized in most countries. In some countries, such as the United States and New Zealand,5 and among socioeconomically disadvantaged, indigenous, and African American subpopulations,12,13 SIDS rates remain unacceptably high. These rates have been linked to the need for ongoing promotion of risk-reduction activities, such as supine sleep position, particularly in communities still experiencing a high SIDS burden.5 For example, despite efforts to promote parents’ and caregivers’ use of a supine position for infant sleep, longitudinal data from the National Infant Sleep Position Study in the United States have demonstrated that a sizable proportion of infants continue to be placed in nonsupine positions for usual sleep (27.9% in 2008).14 Moreover, following consistent increases in the proportion of infants being placed to sleep in supine positions throughout the 1990s, the rates have shown little change since approximately 2001.14Analysis of data from the US Pregnancy Risk Assessment Monitoring System survey has shown that socioeconomic position (SEP), measured by both education level and income, has been consistently, significantly, and positively associated with supine sleep position across states.15 Accordingly, nonsupine sleep position has been associated with socioeconomic deprivation in several other studies.16,17 For example, in a prospective cohort study of sleep position among inner-city mothers of infants aged 3 to 7 months in the United States, Brenner et al.16 found that mothers living below the poverty level were 1.81 times more likely to put their infant to sleep in a prone position than mothers living above the poverty level (95% confidence interval [CI] = 1.10, 2.99). Low SEP was not found to be significantly associated with nonsupine sleep position in an analysis of the National Infant Sleep Position Study; however, this data set underrepresented women with fewer than 12 years of education by more than 50% compared with other national surveys.18,19The size and scope of the population surveyed by the Canadian Maternity Experiences Survey (MES) provided a unique opportunity to pursue our study objectives, which were to (1) clarify the significance of the association between SEP and nonsupine sleep position, and (2) examine patterns of effect modification by SEP on the associations between nonsupine infant sleep position and additional sociodemographic, maternal, infant, and health services predictors.     

Repair of DNA damage induced by the novel nucleoside analogue CNDAG through homologous recombination

We postulate that the deoxyguanosine analogue CNDAG [9-(2-C-cyano-2-deoxy-1-β-d-arabino-pentofuranosyl)guanine] likely causes a single-strand break after incorporation into DNA, similar to the action of its cytosine congener CNDAC, and that subsequent DNA replication across the unrepaired nick would generate a double-strand break. This study aimed at identifying cellular responses and repair mechanisms for CNDAG prodrugs, 2-amino-9-(2-C-cyano-2-deoxy-1-β-d-arabino-pentofuranosyl)-6-methoxy purine (6-OMe) and 9-(2-C-cyano-2-deoxy-1-β-d-arabino-pentofuranosyl)-2,6-diaminopurine (6-NH2). Each compound is a substrate for adenosine deaminase, the action of which generates CNDAG. Growth inhibition assay, clonogenic survival assay, immunoblotting, and cytogenetic analyses (chromosomal aberrations and sister chromatid exchanges) were used to investigate the impact of CNDAG on cell lines. The 6-NH2 derivative was selectively potent in T cell malignant cell lines. Both prodrugs caused increased phosphorylation of ATM and its downstream substrates Chk1, Chk2, SMC1, NBS1, and H2AX, indicating activation of ATM-dependent DNA damage response pathways. In contrast, there was no increase in phosphorylation of DNA-PKcs, which participates in repair of double-strand breaks by non-homologous end-joining. Deficiency in ATM, RAD51D, XRCC3, BRCA2, and XPF, but not DNA-PK or p53, conferred significant clonogenic sensitivity to CNDAG or the prodrugs. Moreover, hamster cells lacking XPF acquired remarkably more chromosomal aberrations after incubation for two cell cycle times with CNDAG 6-NH2, compared to the wild type. Furthermore, CNDAG 6-NH2 induced greater levels of sister chromatid exchanges in wild-type cells exposed for two cycles than those for one cycle, consistent with increased double-strand breaks after a second S phase. CNDAG-induced double-strand breaks are repaired mainly through homologous recombination.     

The impact of behavioral signs of intoxication on bartender service

Objective: The present study was designed to assess whether the serving practices of a sample of bartenders in an American university town would vary as a function of the number of behavioral cues of intoxication displayed by apparently real patrons (who were actually experimental confederates).

Method: We trained two male and three female confederates to role-play three different conditions (three ambiguous signs, eight apparently obvious signs, or no signs of intoxication) and assessed whether they would be served a second beer after ‘accidentally’ knocking over a first beer.

Results: Service of another beer was denied in only 10% of episodes when a confederate displayed no signs or three signs indicative of intoxication; however, confederates were denied service during 50% of episodes when multiple, obvious signs were displayed. Furthermore, neither the type of the establishment, gender of the bartender or gender of the confederate was associated with likelihood of being served the second drink.

Conclusion: Although some bartenders are attentive to multiple behavioral signs of intoxication, we recommend additional research on the most effective combinations of server training and legal measures to reduce further the proportion of intoxicated customers served alcohol, both for their own benefit and the public health.     

Effect of a school-based sun-protection intervention on the development of melanocytic nevi in children

"Kidskin" was a 5-year (1995-1999), school-based intervention trial among first-grade children in Perth, Western Australia. It aimed to assess whether a sun-protection intervention could protect against nevus development on the trunk, face, and arms. Included were a control group, a "moderate intervention" group, and a "high intervention" group. Control schools taught the standard health curriculum, while intervention schools received a specially designed sun-protection curriculum over 4 years. The high intervention group also received program materials over summer vacations when sun exposure was likely to be highest and were offered low-cost sun-protective swimwear. After adjustment for baseline nevus counts and potential confounding, nevus counts on all body sites were slightly lower in both intervention groups relative to the control group at follow-up, although the differences were not statistically significant and the high intervention was no more protective. Children in the moderate and high intervention groups, respectively, had fewer nevi on the back (6%, 95% confidence interval (CI): 0, 12; 4%, 95% CI: -3, 11), chest (boys) (5%, 95% CI: -4, 13; 3%, 95% CI: -8, 14), face (11%, 95% CI: 0, 21; 9%, 95% CI: -6, 21), and arms (8%, 95% CI: -1, 17; 3%, 95% CI: -10, 14).     

Developing a reliable audit instrument to measure the physical environment for physical activity

BACKGROUND: The physical environment plays an important role in influencing participation in physical activity, although which factors of the physical environment have the greatest effect on patterns of activity remain to be determined. We describe the development of a comprehensive instrument to measure the physical environmental factors that may influence walking and cycling in local neighborhoods and report on its reliability. METHODS: Following consultation with experts from a variety of fields and a literature search, we developed a Systematic Pedestrian and Cycling Environmental Scan (SPACES) instrument and used it to collect data over a total of 1987 kilometers of roads in metropolitan Perth, Western Australia. The audit instrument is available from the first author on request. Additional environmental information was collected using desktop methods and geographic information systems (GIS) technology. We assessed inter- and intra-rater reliability of the instrument among the 16 observers who collected the data. RESULTS: The observers reported that the audit instrument was easy to use. Both inter- and intra-rater reliability of the environmental scan instrument were generally high. CONCLUSIONS: Our instrument provides a reliable, practical, and easy-to-use method for collecting detailed "street-level" data on physical environmental factors that are potential influences on walking in local neighborhoods.